rs113684274

chr20-63678280-G-Achr20-63678280-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001283009.2(RTEL1):c.971G>A(p.Arg324His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,612,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 2.71

Genes affected

RTEL1 (HGNC:15888): (regulator of telomere elongation helicase 1) This gene encodes a DNA helicase which functions in the stability, protection and elongation of telomeres and interacts with proteins in the shelterin complex known to protect telomeres during DNA replication. Mutations in this gene have been associated with dyskeratosis congenita and Hoyerall-Hreidarsson syndrome. Read-through transcription of this gene into the neighboring downstream gene, which encodes tumor necrosis factor receptor superfamily, member 6b, generates a non-coding transcript. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

RTEL1-TNFRSF6B (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09220213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.971G>A	p.Arg324His	missense_variant	12/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.1798G>A		non_coding_transcript_exon_variant	12/38
LOC124904954	XR_007067717.1	n.96C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.971G>A	p.Arg324His	missense_variant	12/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000212 AC: 53 AN: 249636 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135114

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1460312 Hom.: 0 Cov.: 36 AF XY: 0.000343 AC XY: 249 AN XY: 726230

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74424

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000570

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2022	- -

Dyskeratosis congenita Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.1043G>A (p.R348H) alteration is located in exon 12 (coding exon 11) of the RTEL1 gene. This alteration results from a G to A substitution at nucleotide position 1043, causing the arginine (R) at amino acid position 348 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 03, 2022

BP4 -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 324 of the RTEL1 protein (p.Arg324His). This variant is present in population databases (rs113684274, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as c.1043G>A (p.Arg348His). ClinVar contains an entry for this variant (Variation ID: 473899). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Sep 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.85	D;T;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.092	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	M;.;M;.
MutationTaster	Benign	0.58	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.074	T;T;T;.
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.068	B;B;B;.
Vest4		0.33
MVP		0.81
ClinPred		0.020	T
GERP RS		0.69
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.042
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113684274; hg19: chr20-62309633;